The 3xe2x80x2,5xe2x80x2-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least eleven different families which are structurally, biochemically and pharmacologically distinct from one another. The enzymes within each family are commonly referred to as isoenzymes, or isozymes. A total of more than fifteen gene products is included within this class, and further diversity results from differential splicing and post-translational processing of those gene products. The present invention relates to the four gene products of the fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and PDE4D, and their inhibition, including selective inhibition of PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family. Further below will be found a more detailed discussion of the genomic organization, molecular structure and enzymatic activity, differential splicing, transcriptional regulation and phosphorylation, distribution and expression, and selective inhibition of the PDE4 isozyme subtypes.
The PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate (cAMP), and by sensitivity to inhibition by rolipram. A number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models. See, e.g., Torphy et al., Environ. Health Perspect. 102 Suppl. 10, 79-84, 1994; Duplantier et al., J. Med. Chem. 39 120-125, 1996; Schneider et al., Pharmacol. Biochem. Behav. 50 211-217, 1995; Banner and Page, Br. J. Pharmacol. 114 93-98, 1995; Barnette et al., J. Pharmacol. Exp. Ther. 273 674-679, 1995; Wright et a!. xe2x80x9cDifferential in vivo and in vitro bronchorelaxant activities of CP-80633, a selective phosphodiesterase 4 inhibitor,xe2x80x9d Can. J. Physiol. Pharmacol. 75 1001-1008, 1997; Manabe et al. xe2x80x9cAnti-inflammatory and bronchodilator properties of KF19514, a phosphodiesterase 4 and 1 inhibitor,xe2x80x9d Eur. J. Pharmacol. 332 97-107, 1997; and Ukita et al. xe2x80x9cNovel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: synthesis and biological activities of a series of 1-pyridyinaphthalene derivatives,xe2x80x9d J. Med. Chem. 42 1088-1099, 1999. Accordingly, there continues to be considerable interest in the art with regard to the discovery of further selective inhibitors of PDE4s.
The present invention is also concerned with the use of selective PDE4 inhibitors for the improved therapeutic treatment of a number of inflammatory, respiratory and allergic diseases and conditions, but especially for the treatment of asthma; chronic obstructive pulmonary disease (COPD) including chronic bronchitis, emphysema, and bronchiectasis; chronic rhinitis; and chronic sinusitis. Heretofore in the art, however, the first-line therapy for treatment of asthma and other obstructive airway diseases has been the nonselective PDE inhibitor theophylline, as well as pentoxifylline and IBMX, which may be represented by Formulas (0.0.1), (0.0.2), and (0.0.3), respectively: 
Theophylline, which has the PDEs as one of its biochemical targets, in addition to its well characterized bronchodilatory activity, affects the vasculature of patients with increased pulmonary artery pressure, suppresses inflammatory cell responses, and induces apoptosis of eosinophils. Theophylline""s adverse events, most commonly cardiac dysrhythmias and nausea, are also mediated by PDE inhibition, however, leading to the search for more selective inhibitors of PDEs that are able to suppress both immune cell functions in vitro and allergic pulmonary inflammation in vivo, while at the same time having improved side-effect profiles. Within the airways of patients suffering from asthma and other obstructive airway diseases, PDE4 is the most important of the PDE isozymes as a target for drug discovery because of its distribution in airway smooth muscle and inflammatory cells. Several PDE4 inhibitors introduced to the art thus far have been designed to have an improved therapeutic index concerning the cardiovascular, gastrointestinal, and central nervous system side effects of the above-mentioned nonselective xanthines.
Airflow obstruction and airway inflammation are features of asthma as well as COPD. While bronchial asthma is predominantly characterized by an eosinophilic inflammation, neutrophils appear to play a major role in the pathogenesis of COPD. Thus, PDEs that are involved in smooth muscle relaxation and are also found in eosinophils as well as neutrophils probably constitute an essential element of the progress of both diseases. The PDEs involved include PDE3s as well as PDE4s, and bronchodilating inhibitors have been discovered which are selective PDE3 inhibitors and dual PDE3/4 selective inhibitors. Examples of these are milrinone, a selective PDE3 inhibitor, as well as zardaverine and benafentrine, both dual PDE3/4 selective inhibitors, which may be represented by Formulas (0.0.4), (0.0.5), and (0.0.6), respectively: 
However, benafentrine results in bronchodilation only when administered by inhalation, and zardaverine produces only a modest and short-lived bronchodilation. Milrinone, a cardiotonic agent, induces short-lived bronchodilation and a slight degree of protection against induced bronchoconstriction, but has marked adverse events, e.g., tachycardia and hypotension. Unsatisfactory results have also been obtained with a weakly selective PDE4 inhibitor, tibenelast, and a selective PDE5 inhibitor, zaprinast, which may be represented by Formulas (0.0.7) and (0.0.8): 
More relative success has been obtained in the art with the discovery and development of selective PDE4 inhibitors.
In vivo, PDE4 inhibitors reduce the influx of eosinophils to the lungs of allergen-challenged animals while also reducing the bronchoconstriction and elevated bronchial responsiveness occurring after allergen challenge. PDE4 inhibitors also suppress the activity of immune cells, including CD4+ T-lymphocytes, monocytes, mast cells, and basophils; reduce pulmonary edema; inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC); potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC); reduce airway smooth muscle mitogenesis; and induce bronchodilation. PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD8+ T-lymphocytes, and neutrophils. PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and, and potentially interfere with the ability of airway epithelial cells to generate pro-inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema.
Selective PDE4 inhibitors which have been discovered thus far that provide therapeutic advantages include SB-207,499, identified as ARIFLO(copyright), which may be represented by Formula (0.1.9): 
SB-207,499, administered orally at dosages of 5, 10, and 15 mg b.i.d., has produced significant increases in trough FEV1 (forced expiratory volume in 1 second) from placebo at week 2 of a study involving a large number of patients. Another potent, selective PDE4 inhibitor, CDP840, has shown suppression of late reactions to inhaled allergen after 9.5 days of oral administration at doses of 15 and 30 mg in a group of patients with bronchial asthma. CDP840 may be represented by Formula (0.0.9): 
PDEs have also been investigated as potential therapy for obstructive lung disease, including COPD. In a large study of SB-207,499 in patients with COPD, the group of patients receiving 15 mg b.i.d. has experienced a progressive improvement in trough FEV1, reaching a maximum mean difference compared with placebo of 160 mL at week 6, which represents an 11% improvement. See Compton et al., xe2x80x9cThe efficacy of Ariflo (SB207499), a second generation, oral PDE4 inhibitor, in patients with COPD,xe2x80x9d Am. J. Respir. Crit. Care Med. 159, 1999. Patients with severe COPD have been observed to have pulmonary hypertension, and decreases in mean pulmonary artery pressure under clinical conditions have been achieved by oral administration of the selective PDE3 inhibitors milrinone and enoximone. Enoximone has also been shown to reduce airway resistance in patients hospitalized with decompensated COPD. See Leeman et al., Chest 91 662-6, 1987. Using selective PDE3 inhibition by motapizone and selective PDE5 inhibition by zaprinast, it has been shown that combined inhibition of PDE 3 and 5 exerts a relaxation of pulmonary artery rings which corresponds broadly to the pattern of PDE isozymes found in the pulmonary artery smooth muscle. See Rabe et al., Am. J. Physiol. 266 (LCMP 10): L536-L543, 1994. The structures of milrinone and zaprinast are shown above as Formulas (0.0.4) and (0.0.8), respectively.
The structures of enoximone and motapizone may be represented by Formulas (0.0.10) and (0.0.11), respectively: 
The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFxcex1) release in eosinophils, neutrophils and monocytes. PDE4 inhibitors may induce emesis, i.e., nausea and vomiting, which, as expected, is an adverse effect. The emesis adverse effect became apparent when PDE4 inhibitors were first investigated for CNS indications such as depression, when rolipram and denbufylline were used in clinical trials. Rolipram and denbufylline may be represented by Formulas (0.0.12) and (0.0.13), respectively: 
The mechanism(s) by which PDE4 inhibitors may potentially induce emesis is/are uncertain, but a study of the PDE4 inhibitor Ro-20-1724 suggests that nausea and vomiting are at least partially mediated by the emesis centers in the brain. Gastrointestinal adverse events may be caused by local effects, e.g., rolipram is a very potent stimulator of acid secretion from gastric parietal cells, and the resulting excess acid, by producing local irritation, may exacerbate gastrointestinal disturbances. Ro-20-1724 may be represented by Formula (0.0.14): 
Efforts to minimize or eliminate the above-mentioned adverse events sometimes associated with PDE4 inhibitors have included creating inhibitors which do not penetrate the central nervous system, and administering PDE4 inhibitors by inhalation rather than orally.
With regard to the PDE4 subtypes, A, B, C, and D, it has been found that PDE4C is usually less sensitive to all inhibitors; whereas, with respect to the subtypes A, B, and D, there is as yet no clear evidence of inhibitor specificity, which is defined as a 10-fold difference in IC50 values. While most inhibitors, especially RS-25,344, are more potent against PDE4D, this does not amount to selectivity. RS-25,344 may be represented by Formula (0.0.15): 
On the other hand, there is a stereoselective effect on the elevation of cAMP in a range of cell types, which has been demonstrated with the results of an investigation of CDP840, shown above as Formula (0.0.9), and its less active enantiomer CT-1731, which is represented by Formula (0.0.16): 
It has been known for some time that rolipram had the ability to interact with a high-affinity binding site on brain membranes, and it was later established in the art that this high-affinity rolipram binding site (Sr), which is distinct from the catalytic site (Sc), exists in a truncated recombinant PDE4A and a full-length recombinant PDE4B. More recently, Sr has been identified on all four PDE4 subtypes. See Hughes et al., Drug Discovery Today 2(3) 89-101, 1997. The presence of Sr appears to have a profound effect on the ability of certain inhibitors such as rolipram and RS-25,344 to inhibit the catalytic activity of PDE4 isozymes.
The impact of residues on inhibitor binding is also significant. A single amino acid substitution (alanine for aspartate) in the catalytic region of PDE4B has been shown to be critical for inhibition by rolipram, and this appears to be a class effect because related inhibitors RP-73,401 and Ro-20-1724 also lose potency on the mutant enzyme. However, the role of binding of inhibitors to the SC or to the Sr, in terms of elevation of cAMP and inhibition of cell responses, is not fully understood at the present time.
RP-73,401, in guinea-pig studies, has been found to be active in (1) the inhibition of antigen-induced lung eosinophilia and eosinophil peroxidase (EPO), Banner, K. H., xe2x80x9cThe effect of selective phosphodiesterase inhibitors in comparison with other anti-asthma drugs on allergen-induced eosinophilia in guinea-pig airways,xe2x80x9d Pulm. Pharmacol. 8 37-42, 1995; (2) antigen-induced bronchoalveolar lavage (BAL) eosinophilia, Raeburn et al., xe2x80x9cAnti-inflammatory and bronchodilator properties of RP73401, a novel and selective phosphodiesterase Type IV inhibitor,xe2x80x9d Br. J. Pharmacol. 113 1423-1431, 1994; (3) antigen-induced airway eosinophilia and platelet activating factor-(PAF)xe2x80x94 and ozone-induced airway hyper-responsiveness (AHR), Karlsson et al., xe2x80x9cAnti-inflammatory effects of the novel phosphodiesterase IV inhibitor RP73401,xe2x80x9d Int. Arch. Allergy Immunol. 107 425-426, 1995; and (4) IL-5 induced pleural eosinophila. Development of RP-73,401, piclamilast, has been discontinued. Piclamilast may be represented by Formula (0.0.17): 
A related series of compounds is represented by RPR-132294 and RPR-132703, which have been demonstrated in rat studies to have activity in the inhibition of antigen-induced bronchospasm; Escott et al., xe2x80x9cPharmacological profiling of phosphodiesterase 4 (PDE4) inhibitors and analysis of the therapeutic ratio in rats and dogs,xe2x80x9d Br. J. Pharmacol. 123(Proc. Suppl.) 40P, 1998; and Thurairatnam et al., xe2x80x9cBiological activity and side effect profile of RPR-132294 and RPR-132703xe2x80x94novel PDE4 inhibitors,xe2x80x9d XVth EFMC Int. Symp. Med. Chem., 1998. The structure of RPR-132294 may be represented by Formula (0.0.18): 
Another compound whose development has been discontinued is WAYxe2x80x94PDA-641, filaminast, which in studies in the dog, has been found to be active in the inhibition of seratonin-induced bronchoconstriction. Filaminast may be represented by Formula (0.0.19): 
It has been suggested in the art that PDE4 inhibitors that have a high affinity at the Sr can be correlated with emesis and increased gastric acid secretion. RS-23,544, RP-73,401, and CP-80,633 elicit emesis and have a high affinity at the Sr. CDP840 and SB-207,499 have a comparatively low affinity at the Sr, but CDP840 has a significantly higher potency at the Sc than does SB-207,499. CDP840 has been demonstrated to provide significant inhibition of late-phase response in the treatment of asthma without any adverse events of nausea or headache. Another PDE4 inhibitor that has been shown to have adverse events of nausea and vomiting is BRL-61,063, also referred to as cipamfylline, which is described further below. The development of CDP840 has been discontinued, while CP-80,633, atizoram, has been advanced into clinical studies. CP-80,633 and BRL-61,063 may be represented by Formulas (0.0.20) and (0.1.12), respectively: 
Another compound which is in development is LAS-31025, arofylline, which in guinea-pig studies, has been found to be active in the inhibition of antigen-induced bronchoconstriction; Beleta, B. J., xe2x80x9cCharacterization of LAS31025: a new selective PDE IV inhibitor for bronchial asthma,xe2x80x9d Third Int. Conf. On Cyclic Nucleotide Phosphodiesterase: From Genes to Therapies, Glasgow, UK, 1996, Abstract 73. LAS-31025, arofylline, may be represented by Formula (0.0.21): 
A number of PDE4 inhibitors have been advanced in development. For example, the effects of V-11294A on LPS-stimulated ex vivo TNF release and PHA induced lymphocyte proliferation have been determined in a randomized, double-blind placebo-controlled study which has found that an oral dose of 300 mg is effective in reducing TNF levels and lymphocyte proliferation; Landells et al., xe2x80x9cOral administration of the phosphodiesterase (PDE) 4 inhibitor, V11294A inhibits ex-vivo agonist-induced cell activation,xe2x80x9d Eur. Resp. J. 12(Suppl. 28) 362s, 1998; and Gale et al., xe2x80x9cPharmacodynamic-pharmacokinetic (PD/PK) profile of the phosphodiesterase (PDE) 4 inhibitor, V11294A, in human volunteers,xe2x80x9d Am. J. Respir. Crit Care Med. 159A611, 1999.
The compound D4418 has been administered to healthy volunteers in a single escalating dose, randomized, placebo-controlled Phase I study; Montana et al., xe2x80x9cActivity of D4418, a novel phosphodiesterase 4 (PDE4) inhibitor, effects in cellular and animal models of asthma and early clinical studies,xe2x80x9d Am. J. Respir. Crit. Care Med. 159 A108, 1999. D4418 is a moderately potent PDE4 inhibitor with an IC50 of 200 nM. It has good oral absorption; a 200 mg dose provides a plasma Cmax of 1.4 xcexcg/ml. D4418 has been discontinued from development due to its moderate potency, and has been replaced by the preclinical development candidate D4396.
V-11294A and D4418 may be represented by Formulas (0.0.22) and (0.0.23), respectively: 
Another compound, CI-1018, has been evaluated in 54 subjects and no adverse events were reported at doses up to 400 mg; Pruniaux et al., xe2x80x9cThe novel phosphodiesterase inhibitor CI-1018 inhibits antigen-induced lung eosinophilia in sensitized brown-norway ratsxe2x80x94comparison with rolipram,xe2x80x9d Inflammation S-04-6, 1999. CI-1018 has been demonstrated to have good oral bioavailability (57% in the rat) and good oral potency of with an ED50 of 5 mg/kg in that same species. CI-1018 is a relatively weak PDE4 inhibitor with an IC50 of 1.1M in U937 cells. CI-1018 has also been identified as, or associated with as closely related in structure to, PD-168787, which in rat studies has been demonstrated to have activity in the inhibition of antigen-induced eosinophilia; Pascal et al., xe2x80x9cSynthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]-diazepino[6,7,1-hi] indolines: novel PDE4 inhibitors,xe2x80x9d 215th ACS, Dallas, USA, MEDI 50, 1998. Inferred structures for CI-1018 and PD-168787 belong to a diazepinone class whose nucleus may be represented by Formula (0.0.24): 
The above-mentioned compounds have also been evaluated in animal models which demonstrate their PDE4 inhibition activity. For example, V-11294A, in guinea-pig studies, has been found to be active in the inhibition of antigen-induced bronchoconstriction; Cavalla et al., xe2x80x9cActivity of Vi 1294A, a novel phosphodiesterase 4 (PDE4) inhibitor, in cellular and animal models of asthma,xe2x80x9d Amer. J. Respir. Crit. Care Med. 155 A660, 1997. D4418, in guinea-pig studies, has been found to be active in the inhibition of antigen-induced early and late phase bronchoconstriction and BAL eosinophilia; Montana, et al., Ibid. CI-1018, in rat studies, has been found to be active in the inhibition of antigen-induced eosinophilia; Burnouf, et al., xe2x80x9cPharmacology of the novel phosphodiesterase Type 4 inhibitor, CI-1018,xe2x80x9d 215th ACS Nat. Meeting, MEDI 008, 1998.
Other compounds which have been advanced in development include CDC-3052, D-22888, YM-58997, and roflumilast, which may be represented by Formulas (0.0.27), (0.0.28), (0.0.29), and (0.0.30), respectively: 
CDC-3052 has been discontinued from development, but has been succeeded by very potent inhibitors of PDE4 such as the compound represented by Formula (0.0.31), and by the anti-inflammatory compound CDC-801 represented by Formula (0.0.32), respectively: 
The compound of Formula (0.0.32) is reported to have IC50 values of 42 pM and 130 nM as an inhibitor of PDE4 and TNF production, respectively; Muller et al., xe2x80x9cN-Phthaloyl beta-aryl-beta-amino derivatives: Potent TNF-alpha and PDE4 inhibitors,xe2x80x9d 217th American Chemical Society, Annheim, Germany, MEDI 200, 1999; and Muller et al., xe2x80x9cThalidomide analogs and PDE4 inhibition,xe2x80x9d Bioorg. Med. Chem. Letts. 8 2669-2674, 1998.
CDC-801 is from a series of compounds based on thalidomide and has been developed primarily to improve the TNF-xcex1 inhibitory activity of thalidomide for the treatment of autoimmune diseases. Thalidomide may be represented by Formula (0.0.33): 
CDC-801 has also been studied for the treatment of Crohn""s disease, a chronic granulomatous inflammatory disease of unknown etiology commonly involving the terminal ileum, with scarring and thickening of the bowel wall which frequently leads to intestinal obstruction and fistula and abscess formation. Crohn""s disease has a high rate of recurrence after treatment.
YM-58997 has an IC50 value of 1.2 nM against PDE4; Takayama et al., xe2x80x9cSynthetic studies on selective Type IV phosphodiesterase (PDE IV) inhibitors,xe2x80x9d 214th American Chemical Society, Las Vegas, USA, MEDI 245, 1997. YM-58997 has a 1,8-naphthyridin-2-one structure, as does YM-976.
Roflumilast has been studied for the treatment of both COPD and asthma, and has an IC50 value of 3.5 nM in standard in vitro guinea-pig models of asthma. The use of roflumilast and a surfactant for the treatment of adult respiratory distress syndrome (ARDS) has also been described.
AWD-12,281, which is now designated as loteprednol, has been shown to be active in a rat model of allergic rhinitis, as described further below in a section which deals with allergic rhinitis and the use of PDE4 inhibitors to treat it. AWD-12,281 may be represented by Formula (0.0.34): 
Compounds related in structure to CDP840, shown further above as Formula (0.0.9), include L-826,141, which has been reported to have activity in a rat model of bronchitis; Gordon et al., xe2x80x9cAnti-inflammatory effects of a PDE4 inhibitor in a rat model of chronic bronchitis,xe2x80x9d Am. J. Respir. Crit. Care Med. 159 A33, 1999. Another such compound is related in structure to those reported in Perrier et al., xe2x80x9cSubstituted furans as inhibitors of the PDE4 enzyme,xe2x80x9d Bioorg. Med. Chem. Letts. 9 323-326, 1999, and is represented by Formula (0.0.35). 
Other compounds which been found to be very potent PDE4 inhibitors are those represented by Formulas (0.0.36), (0.0.37), and (0.0.38): 
Compounds have been created which combine PDE4 and matrix metalloproteinase (MMP) inhibitory activity in a single molecule; Groneberg et al., xe2x80x9cDual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template,xe2x80x9d J. Med. Chem. 42(4) 541-544, 1999. Two examples of such compounds are represented by Formulas (0.0.39) an d (0.0.40): 
The respective IC50 values for the compounds of Formulas (0.1.36) and (0.1.37) using a guinea-pig macrophage PDE4 assay were 1 nM and 30 nM.
The compounds identified as KE19514 and KF17625 have been shown in guinea-pig studies to have activity in the inhibition of the following: histamine-induced and antigen-induced bronchoconstriction; PAF-induced lung eosinophilia and antigen-induced BAL eosinophilia; acetylcholine (ACh)-induced AHR; PAF-induced BAL eosinophilia and neutrophilia, and AHR; antigen-induced bronchospasm; and anaphylactic bronchoconstriction; Fujimura et al., xe2x80x9cBronchoprotective effects of KF-19514 and cilostazol in guinea-pigs in vivo,xe2x80x9d Eur. J. Pharmacol. 327 57-63, 1997; Manabe et al., Ibid.; Manabe et al., xe2x80x9cKF19514, a phosphodiesterase 4 and 1 inhibitor, inhibits PAF-induced lung inflammatory responses by inhaled administration in guinea-pigs,xe2x80x9d Int. Arch. Allergy Immunol. 114 389-399, 1997; Suzuki et al., xe2x80x9cNew bronchodilators. 3. Imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones,xe2x80x9d J. Med. Chem. 35 4866-4874, 1992; Matsuura et al., xe2x80x9cSubstituted 1,8-naphthyridin-2(1H)-ones as selective phosphodiesterase IV inhibitors,xe2x80x9d Biol. Pharm. Bull. 17(4) 498-503, 1994; and Manabe et al., xe2x80x9cPharmacological properties of a new bronchodilator, KF17625,xe2x80x9d Jpn. J. Pharmacol. 58(Suppl. 1) 238P, 1992. KF19514 and KF17625 may be represented by Formulas (0.0.41) and (0.0.42): 
The reported potency and lack of emesis in a series of indandiones suggests that the hypothesis that has related side-effects such as emesis to the ratio of affinity for the PDE4 enzyme relative to that for the high affinity rolipram binding site (HARBS) is erroneous. Such indandiones may be represented by Formulas (0.0.43) and (0.0.44): 
The PDE4 inhibitors that have been created heretofore fall into a significant number of different classes in terms of their chemical structures. Such classes have been as diverse as phenanthridines and naphthyridines. One class of PDE4 inhibitors are lignans such as T-440, which has been demonstrated to have activity in the inhibition of the following: early phase bronchoconstriction induced by antigen, histamine, LTD4, U-46619, Ach, neurokinin A, and endothelin-1; allergen-induced early phase and late phase bronchoconstriction and BAL eosinophilia; and ozone-induced AHR and airway epithelial injury. Optimization of the PDE4 inhibitory potency of such compounds has led to the discovery of T-2585, one of the most potent PDE4 inhibitors described to date with an IC50 value of 0.13 nM against guinea-pig lung PDE4. T-440 and T-2585 may be represented by Formulas (0.0.45) and (0.0.46): 
Another class of PDE4 inhibitors consists of benzofurans and benzothiophenes. In particular, furan and chroman rings have been utilized as surrogates for the cyclopentylether of the rolipram pharmacophore. An example of such a compound is one that is apparently related in structure to BAY 19-8004, and which may be represented by Formula (0.0.47): 
Another benzofuran-type compound has been reported to have an IC50 value of 2.5 nM, and may be represented by Formula (0.0.48): 
A compound with a related structure, which is not, however, a benzofuran, is characterized by a fused dioxicin ring and is reported to produce almost complete inhibition of canine tracheal PDE4 at 100 nM. This compound may be represented by Formula (0.0.49): 
Quinolines and quinolones are a further class of PDE4 inhibitor structures, and they serve as surrogates for the catechol moiety of rolipram. This compound and two compounds of similar structure may be represented by Formulas (0.0.50), (0.0.51), and (0.0.52): 
Purines, xanthines, and pteridines represent yet further classes of chemical compounds to which PDE4 inhibitors described heretofore in the art belong. The compound V-11294A described further above and represented by Formula (0.0.22), is a purine. A PDE4 inhibitor which is a xanthine compound, the class of compounds to which theophylline belongs, has been described in the art; Montana et al., xe2x80x9cPDE4 inhibitors, new xanthine analogues,xe2x80x9d Bioorg. Med. Chem. Letts. 8 2925-2930, 1998. The xanthine compound may be represented by Formula (0.0.54): 
A potent PDE4 inhibitor belonging to the pteridine class of compounds has been demonstrated to have an IC50 value of 16 nM against a PDE4 derived from tumor cells and to inhibit the growth of tumor cells at micromolar concentrations; Merz et al., xe2x80x9cSynthesis of 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth,xe2x80x9d J. Med. Chem. 41(24) 4733-4743, 1998. The pteridine PDE4 inhibitor may be represented by Formula (0.0.55): 
Triazines represent a still further class of chemical compounds to which PDE4 inhibitors belong that have been described in the art heretofore. Two such triazines have been described which display bronchodilator activity and are potent relaxant agents in a guinea-pig trachea model. These compounds, which may be represented by Formulas (0.0.56) and (0.0.57) below, are also moderately potent PDE4 inhibitors with IC50 values of 150 and 140 nM, respectively: 
A triazine having a structure assumed to be closely related to that of the compounds of Formulas (0.0.56) and (0.0.57) is UCB-29936, which has been demonstrated to have activity in a murine model of septic shock; Danhaive et al., xe2x80x9cUCB29936, a selective phosphodiesterase Type IV inhibitor: therapeutic potential in endotoxic shock,xe2x80x9d Am. J. Respir. Crit. Care. Med. 159A611, 1999.
Efforts have also been made in the art to improve the selectivity of PDE4 inhibitors with respect to the A through D subtypes described further above. There are presently four known isoforms (subtypes) of the PDE4 isozyme, encompassing seven splice variants, also described further above. The PDE4D isoform mRNA is expressed in inflammatory cells such as neutrophils and eosinophils, and it has been suggested in the art that D-selective inhibitors of PDE4 will provide good clinical efficacy with reduced side-effects. A nicotinamide derivative displaying selectivity for inhibition of the PDE4D isoform has been described; WO 98/45268; as well as a naphthyridine derivative reported to be a PDE4D selective inhibitor; WO 98/18796. These compounds may be represented by Formulas (0.0.58) and (0.0.59), respectively: 
Another nicotinamide compound has been described in the art which may be useful in the treatment of CNS diseases such as multiple sclerosis; GB-2327675; and a rolipram derivative has been described in the art which is a PDE4 inhibitor which binds with equal affinity to both the catalytic and the HARB sites on human PDE4B2B; Tian et al., xe2x80x9cDual inhibition of human Type 4 phosphodiesterase isostates by (R,R)-(+/xe2x88x92)-methyl-3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-1-pyrrolidine carboxylate,xe2x80x9d Biochemistry 37(19) 6894-6904, 1998. The nicotinamide derivative and the rolipram derivative may be represented by Formulas (0.0.60) and (0.0.61), respectively: 
Further background information concerning selective PDE4 isozymes may be found in publications available in the art, e.g., Norman, xe2x80x9cPDE4 inhibitors 1999,xe2x80x9d Exp. Opin. Ther. Patents 9(8) 1101-1118, 1999 (Ashley Publications Ltd.); and Dyke and Montana, xe2x80x9cThe therapeutic potential of PDE4 inhibitors,xe2x80x9d Exp. Opin. Invest. Drugs 8(9) 1301-1325, 1999 (Ashley Publications Ltd.).
WO 98/45268 (Marfat et al.), published Oct. 15, 1998, discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme. These selective inhibitors are represented by Formula (0.1.1): 
U.S. Pat. No. 4,861,891 (Saccomano et al.), issued Aug. 29, 1989, discloses nicotinamide compounds which function as calcium independent c-AMP phosphodiesterase inhibitors useful as antidepressants, of Formula (0.1.2): 
The nicotinamide nucleus of a typical compound disclosed in this patent is bonded directly to the R1 group, which is defined as 1-piperidyl, 1-(3-indolyl)ethyl, C1-C4 alkyl, phenyl, 1-(1-phenylethyl), or benzyl optionally mono-substituted by methyl, methoxy, chloro or fluoro. The R2 substituent is bicyclo[2.2.1]hept-2-yl or 
where Y is H, F or Cl; and X is H, F, Cl, OCH3, CF3, CN, COOH, xe2x80x94C(xe2x95x90O)(C1-C4) alkoxy, NH(CH3)C(xe2x95x90O)xe2x80x94 (methylcarbamoyl) or N(CH3)2C(xe2x95x90O)xe2x80x94 (dimethylcarbamoyl).
U.S. Pat. No. 4,692,185 (Michaely et al.) discloses herbicides such as those of Formula (0.1.3): 
where R is (C1-C4) alkyl, (C1-C4) haloalkyl, or halo.
EP 550 900 (Jeschke et al.) discloses herbicides and plant nematicides of Formula (0.1.4): 
where n is 0-3; R1 is selected from numerous groups, but is usually H, 6-CH3, or 5-Cl; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl; R1 and R2 is halo, CN, NO2, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, or arylthio; and R4 is alkyl.
EP 500 989 (Mollner et al.) discloses ACE inhibitors of Formula (0.1.5): 
where n is 0-3; R is OH, SH, COOH, NH2, halo, OR4, SR4, COOR4, NHR4 or N(R4)2, where R4 is lower alkyl, optionally substituted aryl, or acyl; R1 is OH, lower alkoxy, optionally substituted aryl lower alkoxy, aryloxy, or disubstituted amino; R2 is lower alkyl or amino lower alkyl; and R1 and R2 is halo, NO2, lower alkyl, halo lower alkyl, aryl lower alkyl, or aryl. Specific embodiments disclosed include compounds such as that of Formula (0.1.6): 
FR 2.140.772 (Aries) discloses compounds asserted to have utility as analgesics, tranquilizers, antipyretics, anti-inflammatories, and antirheumatics, of Formula (0.1.7): 
where R is 1 or 2 substituents chosen from lower alkyl, trihalomethyl, alkoxy, and halo; Rxe2x80x2 is H or alkyl; and Rxe2x80x3 is hydrogen or alkyl.
JP 07 304775 (Otsuka et al.) discloses naphthyridine and pyridopyrazine derivatives which have anti-inflammatory, immunomodulating, analgesic, antipyretic, antiallergic, and antidepressive action. Also disclosed are intermediates of Formula (0.1.8): 
where X may be CH, and R and Rxe2x80x2 are each lower alkyl.
With regard to the disclosures of the above-identified patents and published patent applications, it will be appreciated that only the disclosure of WO 98/45268 (Marfat et al.) concerns the inhibition of PDE4 isozymes. The state of the art also contains information regarding compounds wholly dissimilar in chemical structure to those of Formula (1.0.0) of the present invention, but which, on the other hand, possess biological activity similar to that of the compounds of Formula (1.0.0). Representative patents and published patent applications disclosing said information are illustrated further below.
U.S. Pat. Nos. 5,552,438; 5,602,157; and 5,614,540 (all to Christensen), which all share the same Apr. 2, 1992 priority date, relate to a therapeutic agent identified as ARIFLO(copyright), which is a compound of Formula (0.1.9) and named as indicated below: 
The compound of Formula (0.1.9) falls within the scope of U.S. Pat. No. 5,552,438 which discloses a genus of compounds of Formula (0.1.10): 
where R1xe2x95x90xe2x80x94(CR4R5)rR6 where r=0 and R6xe2x95x90C3-6 cycloalkyl; Xxe2x95x90YR2 where Yxe2x95x90O and R2xe2x95x90xe2x80x94CH3; X2xe2x95x90O; X3xe2x95x90H; and X4=a moiety of partial Formula (0.1.10.1) 
where X5xe2x95x90H; s=0; R1 and R2xe2x95x90CN; and Zxe2x95x90C(O)OR14 where R14xe2x95x90H. The disclosures of U.S. Pat. Nos. 5,602,157 and 5,614,540 differ from that of U.S. Pat. No. 5,552,438 and each other as to the definition of the R3 group, which in the case of the ARIFLO(copyright) compound, is CN. A preferred salt form of the ARIFLO(copyright) compound is disclosed to be the tris(hydroxymethyl)ammonium methane salt.
U.S. Pat. No. 5,863,926 (Christensen et al.) discloses analogs of the ARIFLO(copyright) compound, e.g., that of Formula (0.1.11): 
WO 99/18793 (Webb et al.) discloses a process of making the ARIFLO(copyright) and related compounds. WO 95/00139 (Barnette et al.) claims a compound which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE IV catalytic form which binds rolipram with a high affinity, divided by the IC50 for the form which binds rolipram with a low affinity; but in a dependent claim restricts the scope thereof to a compound which was not known to be a PDE4 inhibitor prior to Jun. 21, 1993.
WO 99/20625 (Eggleston) discloses crystalline polymorphic forms of cipamfylline for treatment of PDE4 and TNF mediated diseases, of Formula (0.1.12): 
WO 99/20280 (Griswold et al.) discloses a method of treating pruritis by administering an effective amount of a PDE4 inhibitor, e.g., a compound of Formula (0.1.13): 
U.S. Pat. No. 5,922,557 (Pon) discloses a CHO-K1 cell line which stably expresses high levels of a full length low-Km cAMP specific PDE4A enzyme, which has, in turn, been used to examine potent PDE4 enzyme inhibitors and compare the rank order of their potencies in elevating cAMP in a whole-cell preparation with their ability to inhibit phosphodiesterase activity in a broken-cell preparation. It is further said to be found that the soluble enzyme inhibition assay described in the prior art does not reflect behavior of the inhibitors acting in vivo. An improved soluble enzyme whole-cell assay is then disclosed which is said to reflect the behavior of inhibitors acting in vivo. It is further disclosed that there exist at least four distinct PDE4 isoforms or subtypes, and that each subtype has been shown to give rise to a number of splice variants, which in themselves can exhibit different cellular localization and affinities for inhibitors.
With regard to the disclosures of the above-identified patents and published patent applications, it will be appreciated that the compounds involved possess the same biological activity as the compounds of Formula (1.0.0). At the same time, however, the artisan will observe that the chemical structures of said compounds disclosed in the prior art are not only diverse from each other but dissimilar to that of the novel compounds of the present invention as well. The state of the art contains still further information regarding compounds which are dissimilar in chemical structure to those of Formula (1.0.0), and which, moreover, do not possess PDE4 inhibitory activity similar to that of the compounds of Formula (1.0.0). Such compounds disclosed in the prior art do, nevertheless, often have therapeutic utility similar to that possessed by the compounds of Formula (1.0.0), i.e., in the treatment of inflammatory, respiratory and allergic diseases and conditions. In particular this is applicable to certain inhibitors of enzymes and antagonists of receptors in the so-called leukotriene pathway. This is especially the case with regard to the leukotrienes LTB4 and LTD4. Accordingly, representative patents and published patent applications disclosing further information of this type are described below.
Arachidonic acid is metabolized by cyclooxygenase-1 and by 5-lipoxygenase. The 5-lipoxygenase pathway leads to the production of leukotrienes (LTs) which contribute to the inflammatory response through their effect on neutrophil aggregation, degranulation and chemotaxis; vascular permeability; smooth muscle contractility; and on lymphocytes. The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, play an important role in the pathogenesis of asthma. The components of the leukotriene pathway which afford targets for therapeutic intervention are illustrated in the following diagram: 
Accordingly, agents which are able to intervene in any of the steps of the 5-lipoxygenase pathway afford an opportunity for therapeutic treatment. An example of one such agent is the 5-lipoxygenase inhibitor, zileuton, a therapeutic agent identified as ZYFLO(copyright) which may be represented by Formula (0.1.14): 
Another such agent is the LTD4 receptor antagonist zafirlukast, a therapeutic agent identified as ACCOLATE(copyright) which may be represented by Formula (0.1.15): 
A further such LTD4 receptor antagonist is montelukast, a therapeutic agent identified as SINGULAIR(copyright) which may be represented by Formula (0.1.16): 
Another type of the above-mentioned therapeutic targets is the LTB4 receptor, and an example of an antagonist for said receptor is BIIL-260, a therapeutic agent which may be represented by Formula (0.1.17): 
Another example of a therapeutic agent which is an LTB4 receptor antagonist is CGS-25019c which maybe represented by Formula (0.1.18): 
Nothing in the above-described state of the art discloses or would suggest to the artisan the novel compounds of the present invention or their PDE4 inhibitory activity and the resulting significant improvement in therapeutic utility and therapeutic index in the treatment of inflammatory, respiratory and allergic diseases and conditions.
The present invention is concerned with novel compounds which have biological activity as inhibitors of the phosphodiesterase so-called xe2x80x9cType IVxe2x80x9d isoenzyme (xe2x80x9cPDE4 isozymexe2x80x9d). Embodiments of the novel compounds of the present invention are active as non-selective inhibitors of the PDE4 isozyme. Other embodiments of said novel compounds have PDE4 isozyme substrate specificity, especially for the D subtype. Said novel compounds having non-selective or D-selective PDE4 inhibitor activity are generally useful in the therapeutic treatment of various inflammatory, allergic, and respiratory diseases and conditions, and they afford in particular a significant improvement in the therapeutic treatment of obstructive respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD).
The present invention relates to a compound of Formula (1.0.0): 
wherein
j is 0 or 1; provided that when j is 0, n must be 2;
k is 0 or 1
m is 1, 2, or 3;
n is 1 or 2;
W1 and W2 are independently xe2x80x94Oxe2x80x94; xe2x80x94S(xe2x95x90O)txe2x80x94, where t is 0, 1, or 2; or xe2x80x94N(R3)xe2x80x94 where R3 has the same meaning as defined below;
Y is xe2x95x90C(R1a)xe2x80x94, where R1a has the same meaning as defined below; or xe2x80x94[Nxe2x86x92(O)k]xe2x80x94 where k is 0 or 1;
where
R1a is a member selected from the group consisting of xe2x80x94H; xe2x80x94F; xe2x80x94Cl; xe2x80x94CN; xe2x80x94NO2; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkynyl; fluorinated-(C1-C3) alkyl; fluorinated-(C1-C3) alkoxy; xe2x80x94OR16; and xe2x80x94C(xe2x95x90O)NR22aR22b;
where
R22a and R22b are each independently xe2x80x94H; xe2x80x94CH3; xe2x80x94CH2CH3; xe2x80x94CH2CH2CH3; xe2x80x94CH2(CH3)2; xe2x80x94CH2CH2CH2CH3; xe2x80x94CH(CH3)CH2CH3; xe2x80x94CH2CH(CH3)2; xe2x80x94C(CH3)3; cyclopropyl; cyclobutyl; or cyclopentyl;
RA and RB are each a member independently selected from the group consisting of xe2x80x94H; xe2x80x94F; xe2x80x94CF3; xe2x80x94(C1-C4) alkyl; xe2x80x94(C3-C7) cycloalkyl; phenyl; and benzyl; wherein said cycloalkyl, phenyl, and benzyl moieties are each independently substituted with 0 to 3 substituents R10;
where
R10 is a member selected from the group consisting of phenyl; pyridyl; xe2x80x94F; xe2x80x94Cl; xe2x80x94CF3; oxo (xe2x95x90O); xe2x80x94OR16; xe2x80x94NO2; xe2x80x94CN; xe2x80x94C(xe2x95x90O)OR16; xe2x80x94Oxe2x80x94C(xe2x95x90O)R16; xe2x80x94C(xe2x95x90O)NR16; R17xe2x80x94Oxe2x80x94C(xe2x95x90O)NR16R17; xe2x80x94NR16R17; xe2x80x94Oxe2x80x94C(xe2x95x90O)NR16R17; xe2x80x94NR16R17; xe2x80x94NR16C(xe2x95x90O)R17; xe2x80x94NR16C(xe2x95x90O)OR17; xe2x80x94NR16S(xe2x95x90O)2R17; and xe2x80x94S(xe2x95x90O)2NR16R17; where said phenyl or pyridyl is substituted by 0 to 3 R11;
where
R11 is xe2x80x94F; xe2x80x94Cl; xe2x80x94CF3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94OH; xe2x80x94(C1-C3) alkoxy; xe2x80x94(C1-C3) alkyl; or xe2x80x94NR16R17;
xe2x80x83and
R16 and R17 are each a member independently selected from the group consisting of xe2x80x94H; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkenyl; xe2x80x94(C3-C6) cycloalkyl; phenyl; benzyl; and pyridyl; wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or pyridyl is substituted by 0 to 3 substituents selected from the group consisting of xe2x80x94F, xe2x80x94Cl, xe2x80x94CF3, xe2x80x94CN, and xe2x80x94(C1-C3) alkyl;
xe2x80x83or
RA and RB are taken together, but only in the case where m is 1, to form a spiro moiety of Formula (1.2.0): 
where
r and s are independently 0 to 4 provided that the sum of r+s is at least 1 but not greater than 5;
xe2x80x83and
XA is selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(R11)xe2x80x94, or C(R11)2xe2x80x94, where each R11 is selected independently of the other and each has the same meaning as defined above; xe2x80x94NR15xe2x80x94, where R15 has the same meaning as defined below; xe2x80x94Oxe2x80x94; and xe2x80x94S(xe2x95x90O)txe2x80x94, where t is 0, 1, or 2;
xe2x80x83and
said Spiro moiety of partial Formula (1.2.0) is substituted as to any one or more carbon atoms thereof, other than that defining XA, by 0 to 3 substituents R14, where R14 has the same meaning as defined below; as to a nitrogen atom thereof by 0 or 1 substituent R15, where R15 has the same meaning as defined below; and as to a sulfur atom thereof by 0 or 2 oxygen atoms;
RC and RD have the same meaning as defined above for RA and RB except that one of them must be xe2x80x94H, and they are selected independently of each other and of RA and RB:
R1 and R2 may individually or together appear on any ring or rings comprising a meaning of the moiety J2 as defined below; and R1 and R2 are each a member independently selected from the group consisting of xe2x80x94H; xe2x80x94F; xe2x80x94Cl; xe2x80x94CN; xe2x80x94NO2; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkynyl; fluorinated-(C1-C3) alkyl; xe2x80x94OR16; and xe2x80x94C(xe2x95x90O)NR22aR22b; where R16, R22a, and R22b have the same meanings as defined above;
R3 is xe2x80x94H; xe2x80x94(C1-C3) alkyl; phenyl; benzyl; or xe2x80x94OR16, where R16 has the same meaning as defined above;
R4, R5 and R6 may individually or together appear on any ring or rings comprising a meaning of the moiety J1 as defined below; and R4, R5 and R6 are each a member independently selected from the group consisting of
the following:
(a) xe2x80x94H; xe2x80x94F; xe2x80x94Cl; xe2x80x94(C2-C4) alkynyl; xe2x80x94R16; xe2x80x94OR16; xe2x80x94S(xe2x95x90O)pR16; xe2x80x94C(xe2x95x90O)R16; xe2x80x94C(xe2x95x90O)OR16; xe2x80x94OC(xe2x95x90O)R16; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(xe2x95x90O)NR16R17; xe2x80x94OC(xe2x95x90O)NR16R17; xe2x80x94NR22aC(xe2x95x90O)NR16R17; xe2x80x94NR22aC(xe2x95x90NR12)NR16R17; xe2x80x94NR22aC(xe2x95x90NCN)NR16R17; xe2x80x94NR22aC(xe2x95x90Nxe2x80x94NO2)NR16R17; xe2x80x94C(xe2x95x90NR22a)NR16R17; xe2x80x94CH2C(xe2x95x90NR22a)NR16R17; xe2x80x94OC(xe2x95x90NR22)NR16R17; xe2x80x94OC(xe2x95x90Nxe2x80x94NO2)NR16R17; xe2x80x94NR16R17; xe2x80x94CH2NR16R17; xe2x80x94NR22aC(xe2x95x90O)R16; xe2x80x94NR22aC(xe2x95x90O)OR16; =NOR16; xe2x80x94NR22aS(xe2x95x90O)pR17xe2x80x94S(xe2x95x90O)pNR16R17; and xe2x80x94CH2C (xe2x95x90NR22a)NR16R17;
where
p is 0, 1, or 2; and R22aR16, and R17 have the same meanings as defined above;
(b) xe2x80x94(C1-C4) alkyl; and xe2x80x94(C1-C4) alkoxy in the case where one or more of R4, R5, or R6 has the meaning of xe2x80x94OR16 under (a) above and R16 is defined as xe2x80x94(C1-C4) alkyl; wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents xe2x80x94F or xe2x80x94Cl; or 0 or 1 substituent (C1-C2) alkoxycarbonyl-; (C1-C2) alkylcarbonyl-; or (C1-C2) alkylcarbonyloxy-;
xe2x80x83and
(c) an aryl or heterocyclyl moiety selected from the group consisting of phenyl; benzyl; furanyl; tetrahydrofuranyl; oxetanyl; thienyl; tetrahydrothienyl; pyrrolyl; pyrrolidinyl; oxazolyl; oxazolidinyl; isoxazolyl; isoxazolidinyl; thiazolyl; thiazolidinyl; isothiazolyl; isothiazolidinyl; pyrazolyl; pyrazolidinyl; oxadiazolyl; thiadiazolyl; imidazolyl; imidazolidinyl; pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; piperidinyl; piperazinyl; triazolyl; triazinyl; tetrazolyl; pyranyl; azetidinyl; morpholinyl, parathiazinyl; indolyl; indolinyl; benzo[b]furanyl; 2,3-dihydrobenzofuranyl; 2-H-chromenyl; chromanyl; benzothienyl; 1-H-indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzthiazolyl; quinolinyl; isoquinolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; and purinyl; wherein said aryl and heterocyclyl moieties are each independently substituted with 0 to 2 substituents R14 
where
R14 is a member selected from the group consisting of xe2x80x94(C1-C4) alkyl; xe2x80x94(C3-C7) cycloalkyl; phenyl; benzyl; pyridyl; and quinolinyl; where said alkyl, cycloalkyl, phenyl, benzyl, pyridyl, or quinolinyl is substituted by 0, 1, or 2 substituents xe2x80x94F, xe2x80x94Cl, xe2x80x94CH3, xe2x80x94OR16, xe2x80x94NO2, xe2x80x94CN, or xe2x80x94NR16R17; and said R14 group further consists of xe2x80x94F; xe2x80x94Cl; xe2x80x94CF3; oxo (xe2x95x90O); xe2x80x94OR16; xe2x80x94NO2; xe2x80x94CN; xe2x80x94C(xe2x95x90O)OR16; xe2x80x94Oxe2x80x94C(xe2x95x90O)R16; xe2x80x94C(xe2x95x90O)NR16R17; xe2x80x94Oxe2x80x94C(xe2x95x90O)NR16R17; xe2x80x94NR16R17; xe2x80x94NR16C(xe2x95x90O)R17; xe2x80x94NR16C(xe2x95x90O)OR17; xe2x80x94NR16S(xe2x95x90O)2R17; or xe2x80x94S(xe2x95x90O)2NR16R17; where R16 and R17 have the same meanings as defined above;
and further where
R15 is a member independently selected from the group consisting of xe2x80x94H; xe2x80x94NR16R17; xe2x80x94C(xe2x95x90O)R16; xe2x80x94OR16; xe2x80x94(C1-C4) alkyl-OR16; xe2x80x94C(xe2x95x90O)OR16; xe2x80x94(C1-C2) alkyl-C(xe2x95x90O)OR16; xe2x80x94C(xe2x95x90O)NR16R17; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkenyl; xe2x80x94(CH2)u,xe2x80x94(C3-C7) cycloalky where u is 0, 1 or 2; phenyl; benzyl; pyridyl; and quinolinyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl, pyridyl or quinolinyl is substituted with 0 to 3 substituents R12; where R16 and R17 have the same meanings as defined above; and
where
R12 is a member independently selected from the group consisting of xe2x80x94F; xe2x80x94Cl; xe2x80x94CO2R18; xe2x80x94OR16; xe2x80x94CN; xe2x80x94C(xe2x95x90O)NR18R19; xe2x80x94NR18R19; xe2x80x94NR18C(xe2x95x90O)R19; xe2x80x94NR18C(xe2x95x90O)OR19; xe2x80x94NR18S(xe2x95x90O)pR19; xe2x80x94S(xe2x95x90O)pNR18R19, where p is 1 or 2; xe2x80x94(C1-C4) alkyl; and xe2x80x94(C1-C4) alkoxy in the case where R12 has the meaning of xe2x80x94OR16 above and R16 is defined as xe2x80x94(C1-C4) alkyl; wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents independently selected from xe2x80x94F; xe2x80x94Cl; xe2x80x94(C1-C2) alkoxycarbonyl; xe2x80x94(C1-C2) alkylcarbonyl; and xe2x80x94(C1-C2) alkylcarbonyloxy; where R16 has the same meaning as defined above; and
where
R18 and R19 are independently selected from the group consisting of xe2x80x94H; xe2x80x94(C1-C4) alkyl; and phenyl; where said alkyl or phenyl is substituted by 0-3 of xe2x80x94F; or xe2x80x94Cl;
or in the case where J1 is phenyl
(d) R5 and R6 are taken together to form a moiety which is a member selected from the group consisting of partial Formulas (1.3.1) through (1.3.15): 
wherein
R20 and R21 are each a member independently selected from the group consisting of xe2x80x94H; xe2x80x94F; xe2x80x94Cl; xe2x80x94CH3; xe2x80x94CH2F; xe2x80x94CHF2; xe2x80x94CF3; xe2x80x94OCH3; and xe2x80x94OCF3;
R23 and R24 are each independently xe2x80x94H; xe2x80x94CH3; xe2x80x94OCH3; xe2x80x94CH2CH3; xe2x80x94OCH2CH3; xe2x80x94CH2CH2CH3; xe2x80x94CH2(CH3)2; xe2x80x94CH2CH2CH2CH3; xe2x80x94CH(CH3)CH2CH3; xe2x80x94CH2CH(CH3)2; xe2x80x94C(CH3)3; or absent, in which case the dashed line - - - - represents a double bond;
J1 is a moiety comprising a saturated or unsaturated carbon ring system that is a 3- to 7-membered monocyclic, or that is a 7- to 12-membered, fused polycyclic; provided that J1 is not a discontinuous or restricted biaryl moiety; and wherein optionally one carbon atom of said carbon ring system may be replaced by a heteroatom selected from N, O, and S; where optionally a second carbon atom thereof, and further optionally a third carbon atom thereof may be replaced by N;
wherein
said moiety defining J1 is substituted on any ring or rings thereof by R4, R5 and R6, which have the same meaning as defined above;
J2 is a moiety comprising a saturated or unsaturated carbon ring system that is a 3- to 7-membered monocyclic, or that is a 7- to 12-membered, fused polycyclic; provided that J2 is not a discontinuous or restricted biaryl moiety; and wherein optionally one carbon atom of said carbon ring system may be replaced by a heteroatom selected from N, O, and S; where optionally a second carbon atom thereof, and further optionally a third carbon atom thereof may be replaced by N;
wherein
said moiety defining J2 is substituted on any ring or rings thereof by R1 and R2, which have the same meaning as defined above;
D is a member independently selected from the group consisting of
the following
(a) the group consisting of partial Formulas (1.1.1) through (1.1.9): 
wherein
xe2x80x9c*xe2x80x9d indicates the point of attachment of each partial Formula (1.1.1) through (1.1.9) to the remaining portion of Formula (1.0.0);
q is 1, 2, or 3, provided that where q is 2 or 3, R9 has the meaning of xe2x80x94H in at least one instance, or two instances, respectively;
v 0 or 1;
W3 is xe2x80x94Oxe2x80x94; xe2x80x94N(R9)xe2x80x94, where R9 has the same meaning as defined below; or xe2x80x94OC(xe2x95x90O)xe2x80x94;
R7 is a member independently selected from the group consisting of
the following:
(1) xe2x80x94H;
(2) xe2x80x94(C1-C6) alkyl; xe2x80x94(C2-C6) alkenyl; or xe2x80x94(C2-C6) alkynyl; where said alkyl, alkenyl or alkynyl is substituted by 0 to 3 substituents R10, where R10 has the same meaning as defined above;
(3) xe2x80x94(CH2)uxe2x80x94(C3-C7) cycloalkyl where u is 0, 1 or 2; and further where said (C3-C7) cycloalkyl is substituted by 0 to 3 substituents R10 where R10 has the same meaning as defined above;
xe2x80x83and
(4) phenyl or benzyl, where said phenyl or benzyl is independently substituted by 0 to 3 substituents R10 where R10 has the same meaning as defined above;
R8 is a member independently selected from the group consisting of
the following:
(1) phenyl; tetrazol-5-yl; 1,2,4-triazol-3-yl; 1,2,4-triazol-3-on-5-yl; 1,2,3-triazol-5-yl; imidazol-2-yl; imidazol4-yl; imidazolidin-2-on-4-yl; 1,3,4-oxadiazolyl; 1,3,4-oxadiazol-2-on-5-yl; 1,2,4-oxadiazol-3-yl; 1,2,4-oxadiazol-5-on-3-yl; 1,2,4-oxadiazol-5-yl; 1,2,4-oxadiazol-3-on-5-yl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; morpholinyl; parathiazinyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrrolyl; pyrazolyl; succinimidyl; glutarimidyl; pyrrolidonyl; 2-piperidonyl; 2-pyridonyl; 4-pyridonyl; pyridazin-3-onyl; pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl;
xe2x80x83and
(2) indolyl; indolinyl; isoindolinyl; benzo[b]furanyl; 2,3-dihydrobenzofuranyl; 1,3-dihydroisobenzofuranyl; 2H-1-benzopyranyl; 2-H-chromenyl; chromanyl; benzothienyl; 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl; phthalazinyl; 1,8-naphthyridinyl; quinolinyl; isoquinolinyl; quinazolinyl; quinoxalinyl; pyrazolo[3,4-d]pyrimidinyl; pyrimido[4,5-d]pyrimidinyl; imidazo[1,2-a]pyridinyl; pyridopyridinyl; pteridinyl; and 1H-purinyl;
where
any moiety recited in (1) or (2) above is optionally substituted with respect to (i) any one or more carbon atoms thereof optionally by a substituent R14 where R14 has the same meaning as defined above; (ii) any one or more nitrogen atoms thereof that is not a point of attachment of said moiety, optionally by a substituent R15 where R15 has the same meaning as defined above, and all tautomer forms thereof; and (iii) any sulfur atom thereof that is not a point of attachment of said moiety, by 0, 1, or 2 oxygen atoms;
R9 is a member selected from the group consisting of xe2x80x94H; xe2x80x94(C1-C4) alkyl; xe2x80x94(C3-C7) cycloalkyl; phenyl; benzyl; pyridyl; xe2x80x94C(xe2x95x90O)OR16; xe2x80x94C(xe2x95x90O)R16; xe2x80x94OR16; xe2x80x94(C1-C2) alkyl-OR16; and xe2x80x94(C1-C2) alkyl-C(xe2x95x90O)OR16; where R16 has the same meaning as defined above;
and D is further selected from
(b) a moiety comprising a member selected from the group consisting of xe2x80x94Oxe2x80x94 P(xe2x95x90O)(OH)2 (phosphoric); xe2x80x94PH(xe2x95x90O)OH (phosphinic); xe2x80x94P(xe2x95x90O)(OH)2 (phosphonic); xe2x80x94[P(xe2x95x90O)(OH)xe2x80x94O(C1-C4) alkyl] (alkylphosphono); xe2x80x94P(xe2x95x90O)(OH)xe2x80x94O(C1-C4) alkyl) (alkylphosphinyl); xe2x80x94P(xe2x95x90O)(OH)NH2 (phosphoramido); xe2x80x94P(xe2x95x90O)(OH)NH(C1-C4) alkyl and xe2x80x94P(xe2x95x90O)(OH)NHR25 (substituted phosphoramido); xe2x80x94Oxe2x80x94S(xe2x95x90O)2OH (sulfuric); xe2x80x94S(xe2x95x90O)2OH (sulfonic); xe2x80x94S(xe2x95x90O)2NHR26 or xe2x80x94NHS(xe2x95x90O)2R26 (sulfonamido) where R26 is xe2x80x94CH3, xe2x80x94CF3, or o-toluyl; and acylsulfonamido selected from the group consisting of xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2R25; xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2N H2; xe2x80x94C(xe2x95x90O)N HS(xe2x95x90O)2(C1-C4) alkyl; xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2NH(C1-C4) alkyl; xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2N[(C1-C4) alkyl]2; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90O)(C1-C4) alkyl; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90O)NH2; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90O)NH(C1-C4) alkyl; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90O)N[(C1-C4) alkyl]2; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90O)R25; xe2x80x94S(xe2x95x90O)2NHCN; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90S)NH2; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90S)NH(C1-C4) alkyl; xe2x80x94S(xe2x95x90O)2NHC(xe2x95x90S)N[(C1-C4) alkyl]2; and xe2x80x94S(xe2x95x90O)2NHS(xe2x95x90O)2R25;
where
R25 is xe2x80x94H; xe2x80x94(C1-C4) alkyl; phenyl; or xe2x80x94OR18, where R18 has the same meaning as defined above;
or
a pharmaceutically acceptable salt thereof.
The present invention is concerned in particular with a compound of Formula (1.0.0) as above-recited wherein the moiety D comprises as a preferred meaning of R7, phenyl, benzyl, or cyclohexyl illustrated in partial Formulas (1.1.45) through (1.1.47) below; or the moiety D comprises R8 of partial Formula (1.1.4) where v is 0 or 1, comprising a member selected from the group consisting of partial Formulas (1.1.11) through (1.1.44) illustrated below: 
wherein xe2x80x9c*xe2x80x9d indicates the point of attachment of each partial Formula (1.1.1 1) through (1.1.47) to the remaining portion of Formula (1.0.0); and wherein each carbon atom of partial Formulas (1.1.11) through (1.1.44) is optionally substituted by a substituent R14; where R14 and R15 have the same meaning as defined above; and all tautomer forms, and optionally N-oxide forms, thereof; and further wherein each carbon atom of partial Formulas (1.1.45) through (1.1.47) is optionally substituted by a substituent R10; where R10 has the same meaning as defined above.
The present invention is further concerned more particularly with a compound of Formula (1.0.0) as above-recited wherein the moiety D is especially the below-indicated member selected from the above-recited group consisting of partial Formulas (1.1.1 1) through (1.1.47): 
The present invention is further concerned in particular with a compound of Formula (1.0.0) as above-recited wherein the moiety D comprises R8 of partial Formula (1.1.4) where v is 0 or 1, and R8 of said partial Formula (1.1.4) is a member selected from the group consisting of partial Formulas (1.4.1) through (1.4.28): 
where xe2x80x9c*xe2x80x9d indicates the point of attachment to the remaining portion of Formula (1.0.0); and where each carbon atom is optionally substituted by a substituent R14; and where R14 and R15 have the same meaning as defined above; and all tautomer forms, and optionally N-oxide forms, thereof.
The present invention is further concerned with a compound of Formula (1.0.0) wherein J1 comprises especially a member selected from the group consisting of phenyl; pyrrolyl; pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidinyl, piperazinyl; imidazolyl; imidazolidinyl; oxazolyl; isoxazolyl; morpholinyl; thiazolyl; indolyl; quinolinyl; isoquinolinyl; benzimidazolyl; benzoxazolyl; quinuclidinyl; and azabicyclo[3.3.0]octanyl; a monocyclic xe2x80x94(C3-C7) cycloalkyl moiety; a monocyclic xe2x80x94(C5-C7) cycloalkenyl moiety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cycloheptenyl; and a bicyclic xe2x80x94(C7-C10) cycloalkyl or xe2x80x94(C7-C10) cycloalkenyl moiety that is a member selected from the group consisting of norbornanyl, norbornanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1]nonanyl, cyclodecanyl, and adamantanyl.
The present invention is still further concerned especially with a compound of Formula (1.0.0) wherein particularly J1 and the substituents R4, R5, and R6 are selected in such a way that the left-hand terminus of said compound of Formula (1.0.0) is represented by the following partial Formulas (2.0.1) through (2.0.72): 
The present invention is further concerned with a compound of Formula (1.0.0) wherein J2 comprises especially a member selected from the group consisting of phenyl; pyrrolyl; pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidinyl; piperazinyl; imidazolyl; imidazolidinyl; oxazolyl; isoxazolyl; thiazolyl; indolyl; quinolinyl; isoquinolinyl; benzimidazolyl; benzoxazolyl; morpholinyl; quinuclidinyl; and azabicyclo[3.3.0]octanyl; a monocyclic xe2x80x94(C3-C7) cycloalkyl moiety; a monocyclic xe2x80x94(C5-C7) cycloalkenyl moiety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cycloheptenyl; and a bicyclic xe2x80x94(C7-C10) cycloalkyl or xe2x80x94(C7-C10) cycloalkenyl moiety that is a member selected from the group consisting of norbornanyl, norbornenyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1]nonanyl, cyclodecanyl, and adamantanyl.
The present invention is also further concerned especially with a compound of Formula (1.0.0) wherein particularly J2 and the substituents R1 and R2 are selected in such a way that this portion of the right-hand terminus of said compound of Formula (1.0.0) is represented by the following partial Formulas (2.5.1) through (2.5.50) set out below. 
The present invention is still further concerned with a compound of Formula (1.0.0) characterized as to the right-hand side thereof, where m is 1, by partial Formula (1.0.5): 
where xe2x80x9c*xe2x80x9d is a symbol representing the point of attachment of the group of partial Formula (1.0.5) to the remaining portion of a compound of Formula (1.0.0) where RA and R8 are both xe2x80x94H, or one is xe2x80x94H and the other is xe2x80x94CH3, or both are xe2x80x94CH3, or both are taken together to form spiro-cyclopropyl or spiro-cyclobutyl; R1 is xe2x80x94H, xe2x80x94OCH3, or 2xe2x80x2xe2x80x94F; R2 is xe2x80x94H; and the moieties J2 and D are selected such that, said group of partial Formula (1.0.5) is a member selected from the group consisting of partial Formulas (1.5.1) through (1.5.54), as set out below. Where the moiety J2 is phenyl, the 2xe2x80x2-position thereof is located as indicated in partial Formula (1.5.1): 
wherein
xe2x80x9c*xe2x80x9d indicates the point of attachment of each said group of partial Formula (1.0.5) represented by partial Formulas (1.5.1) through (1.5.54) to the remaining portion of Formula (1.0.0).
The present invention is further concerned with a method of treating a subject suffering from a disease or condition mediated by the PDE4 isozyme in its role of regulating the activation and degranulation of human eosinophils, comprising administering to said subject in need of said treatment a therapeutically effective amount of a compound of Formula (1.0.0) as described above. Similarly, the present invention is also concerned with a pharmaceutical composition for use in such a therapeutic treatment, comprising a compound of Formula (1.0.0) as described above together with a pharmaceutically acceptable carrier.
The present invention relates to PDE4 isozyme inhibitors comprising a compound of , Formula (1.0.0) as described above which is useful in treating or preventing one or members selected from the groups of diseases, disorders, and conditions consisting of:
asthma of whatever type, etiology, or pathogenesis; or asthma that is a member selected from the group consisting of atopic asthma; non-atopic asthma; allergic asthma; atopic, bronchial, IgE-mediated asthma; bronchial asthma; essential asthma; true asthma; intrinsic asthma caused by pathophysiologic disturbances; extrinsic asthma caused by environmental factors; essential asthma of unknown or inapparent cause; non-atopic asthma; bronchitic asthma; emphysematous asthma; exercise-induced asthma; occupational asthma; infective asthma caused by bacterial, fungal, protozoal, or viral infection; non-allergic asthma; incipient asthma; wheezy infant syndrome;
chronic or acute bronchoconstriction; chronic bronchitis; small airways obstruction; and emphysema;
obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis; or an obstructive or inflammatory airways disease that is a member selected from the group consisting of asthma; pneumoconiosis; chronic eosinophilic pneumonia; chronic obstructive pulmonary disease (COPD); COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith; COPD that is characterized by irreversible, progressive airways obstruction; adult respiratory distress syndrome (ARDS), and exacerbation of airways hyper-reactivity consequent to other drug therapy;
pneumoconiosis of whatever type, etiology, or pathogenesis; or pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers"" disease; anthracosis or miners"" asthma; asbestosis or steam-fitters"" asthma; chalicosis or flint disease; ptilosis caused by inhaling the dust from ostrich feathers; siderosis caused by the inhalation of iron particles; silicosis or grinders"" disease; byssinosis or cotton-dust asthma; and talc pneumoconiosis;
bronchitis of whatever type, etiology, or pathogenesis; or bronchitis that is a member selected from the group consisting of acute bronchitis; acute laryngotracheal bronchitis; arachidic bronchitis; catarrhal bronchitis; croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; staphylococcus or streptococcal bronchitis; and vesicular bronchitis;
bronchiectasis of whatever type, etiology, or pathogenesis; or bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis; sacculated bronchiectasis; fusiform bronchiectasis; capillary bronchiectasis; cystic bronchiectasis; dry bronchiectasis; and follicular bronchiectasis;
seasonal allergic rhinitis; or perennial allergic rhinitis; or sinusitis of whatever type, etiology, or pathogenesis; or sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis; acute or chronic sinusitis; and ethmoid, frontal, maxillary, or sphenoid sinusitis;
rheumatoid arthritis of whatever type, etiology, or pathogenesis; or rheumatoid arthritis that is a member selected from the group consisting of acute arthritis; acute gouty arthritis; chronic inflammatory arthritis; degenerative arthritis; infectious arthritis; Lyme arthritis; proliferative arthritis; psoriatic arthritis; and vertebral arthritis;
gout, and fever and pain associated with inflammation;
an eosinophil-related disorder of whatever type, etiology, or pathogenesis; or an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia; pulmonary infiltration eosinophilia; Loffler""s syndrome; chronic eosinophilic pneumonia; tropical pulmonary eosinophilia; bronchopneumonic aspergillosis; aspergilloma; granulomas containing eosinophils; allergic granulomatous angiitis or Churg-Strauss syndrome; polyarteritis nodosa (PAN); and systemic necrotizing vasculitis;
atopic dermatitis; or allergic dermatitis; or allergic or atopic eczema;
urticaria of whatever type, etiology, or pathogenesis; or urticaria that is a member selected from the group consisting of immune-mediated urticaria; complement-mediated urticaria; urticariogenic material-induced urticaria; physical agent-induced urticaria; stress-induced urticaria; idiopathic urticaria; acute urticaria; chronic urticaria; angioedema; cholinergic urticaria; cold urticaria in the autosomal dominant form or in the acquired form; contact urticaria; giant urticaria, and papular urticaria;
conjunctivitis of whatever type, etiology, or pathogenesis; or conjunctivitis that is a member selected from the group consisting of actinic conjunctivitis; acute catarrhal conjunctivitis; acute contagious conjunctivitis; allergic conjunctivitis; atopic conjunctivitis; chronic catarrhal conjunctivitis; purulent conjunctivitis; and vernal conjunctivitis
uveitis of whatever type, etiology, or pathogenesis; or uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea; anterior uveitis; iritis; cyclitis; iridocyclitis; granulomatous uveitis; nongranulomatous uveitis; phacoantigenic uveitis; posterior uveitis; choroiditis; and chorioretinitis;
psoriasis;
multiple sclerosis of whatever type, etiology, or pathogenesis; or multiple sclerosis that is a member selected from the group consisting of primary progressive multiple sclerosis; and relapsing remitting multiple sclerosis;
autoimmune/inflammatory diseases of whatever type, etiology, or pathogenesis; or an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders; hemolytic anemia; aplastic anemia; pure red cell anemia; idiopathic thrombocytopenic purpura; systemic lupus erythematosus; polychondritis; scleroderma; Wegner""s granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Stevens-Johnson syndrome; idiopathic sprue; autoimmune inflammatory bowel diseases; ulcerative colitis; Crohn""s disease; endocrin opthamopathy; Grave""s disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; primary biliary cirrhosis; juvenile diabetes or diabetes mellitus type l; anterior uveitis; granulomatous or posterior uveitis; keratoconjunctivitis sicca; epidemic keratoconjunctivitis; diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; psoriatic arthritis; glomerulonephritis with and without nephrotic syndrome; acute glomerulonephritis; idiopathic nephrotic syndrome; minimal change nephropathy; inflammatory/hyperproliferative skin diseases; psoriasis; atopic dermatitis; contact dermatitis; allergic contact dermatitis; benign familial pemphigus; pemphigus erythematosus; pemphigus foliaceus; and pemphigus vulgaris;
prevention of allogeneic graft rejection following organ transplantation;
inflammatory bowel disease (IBD) of whatever type, etiology, or pathogenesis; or inflammatory bowel disease that is a member selected from the group consisting of ulcerative colitis (UC); collagenous colitis; colitis polyposa; transmural colitis; and Crohn""s disease (CD);
septic shock of whatever type, etiology, or pathogenesis; or septic shock that is a member selected from the group consisting of renal failure; acute renal failure; cachexia; malarial cachexia; hypophysial cachexia; uremic cachexia; cardiac cachexia; cachexia suprarenalis or Addison""s disease; cancerous cachexia; and cachexia as a consequence of infection by the human immunodeficiency virus (HIV);
liver injury;
pulmonary hypertension; and hypoxia-induced pulmonary hypertension;
bone loss diseases; primary osteoporosis; and secondary osteoporosis;
central nervous system disorders of whatever type, etiology, or pathogenesis; or a central nervous system disorder that is a member selected from the group consisting of depression; Parkinson""s disease; learning and memory impairment; tardive dyskinesia; drug dependence; arteriosclerotic dementia; and dementias that accompany Huntington""s chorea, Wilson""s disease, paralysis agitans, and thalamic atrophies;
infection, especially infection by viruses wherein such viruses increase the production of TNF-xcex1 in their host, or wherein such viruses are sensitive to upregulation of TNF-xcex1 in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1, HIV-2, and HIV-3; cytomegalovirus, CMV; influenza; adenoviruses; and Herpes viruses, including Herpes F+zoster and Herpes simplex;
yeast and fungus infections wherein said yeast and fungi are sensitive to upregulation by TNF-xcex1 or elicit TNF-xcex1 production in their host, e.g., fungal meningitis; particularly when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but are not limited to, polymixins, e.g., Polymycin B; imidazoles, e.g., clotrimazole, econazole, miconazole, and ketoconazole; triazoles, e.g., fluconazole and itranazole; and amphotericins, e.g., Amphotericin B and liposomal Amphotericin B.
ischemia-reperfusion injury; autoimmune diabetes; retinal autoimmunity; chronic lymphocytic leukemia; HIV infections; lupus erythematosus; kidney and ureter disease; urogenital and gastrointestinal disorders; and prostate diseases.
In particular, the compounds of Formula (1.0.0) are useful in the treatment of (1) inflammatory diseases and conditions comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory diseases and conditions comprising: asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease, and silicosis; (3) infectious diseases and conditions comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune diseases and conditions comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) other diseases and conditions comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia.
The present invention still further relates to the combination of a compound of Formula (1.0.0) together with one or more members selected from the group consisting of the following: (a) leukotriene biosynthesis inhibitors: 5-lipoxygenase (5-LO) inhibitors and 5-lipoxygenase activating protein (FLAP) antagonists selected from the group consisting of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8); 2,6-di-tert-butylphenol hydrazones of Formula (5.2.10); the class of methoxytetrahydropyrans which includes Zeneca ZD-2138 of Formula (5.2.11); the compound SB-210661 of Formula (5.2.12) and the class to which it belongs; the class of pyridinyl-substituted 2-cyanonaphthalene compounds to which L-739,010 belongs; the class of 2-cyanoquinoline compounds to which L-746,530 belongs; the classes of indole and quinoline compounds to which MK-591, MK-886, and BAY x 1005 belong; (b) receptor antagonists for leukotrienes LTB4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-one class of compounds to which L-651,392 belongs; the class of amidino compounds to which CGS-25019c belongs; the class of benzoxaolamines to which ontazolast belongs; the class of benzenecarboximidamides to which BIIL 284/260 belongs; and the classes of compounds to which zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195 belong; (c) PDE4 inhibitors including inhibitors of the isoform PDE4D; (d) 5-Lipoxygenase (5-LO) inhibitors; or 5-lipoxygenase activating protein (FLAP) antagonists; (e) dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF); (f) leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4; (g) antihistaminic H1 receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; (h) gastroprotective H2 receptor antagonists; (i) xcex11- and xcex12-adrenoceptor agonist vasoconstrictor sympathomimetic agents administered orally or topically for decongestant use, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethyinorepinephrine hydrochloride; (i) xcex11- and xcex12-adrenoceptor agonists in combination with inhibitors of 5-lipoxygenase (5-LO); (k) anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine; (I) xcex21- to xcex24-adrenoceptor agonists including metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; (m) methylxanthanines including theophylline and aminophylline; (n) sodium cromoglycate; (O) muscarinic receptor (M1, M2, and M3) antagonists; (p) COX-1 inhibitors (NSAIDs); COX-2 selective inhibitors including rofecoxib; and nitric oxide NSAIDs; (q) insulin-like growth factor type I (IGF-1) mimetics; (r) ciclesonide; (s) inhaled glucocorticoids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate; (t) tryptase inhibitors; (u) platelet activating factor (PAF) antagonists; (v) monoclonal antibodies active against endogenous inflammatory entities; (w) IPL 576; (x) anti-tumor necrosis factor (TNFxcex1) agents including Etanercept, Infliximab, and D2E7; (y) DMARDs including Leflunomide; (z) TCR peptides; (aa) interleukin converting enzyme (ICE) inhibitors; (bb) IMPDH inhibitors; (cc) adhesion molecule inhibitors including VLA-4 antagonists; (dd) cathepsins; (ee) MAP kinase inhibitors; (ff) glucose-6 phosphate dehydrogenase inhibitors; (gg) kinin-B1- and B2-receptor antagonists; (hh) gold in the form of an aurothio group together with various hydrophilic groups; (ii) immunosuppressive agents, e.g., cyclosporine, azathioprine, and methotrexate; (jj) anti-gout agents, e.g., colchicine; (kk) xanthine oxidase inhibitors, e.g., allopurinol; (ll) uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone; (mm) antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine; (nn) growth hormone secretagogues; (oo) inhibitors of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11); (pp) transforming growth factor (TGFxcex2); (qq) platelet-derived growth factor (PDGF); (rr) fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (ss) granulocyte macrophage colony stimulating factor (GM-CSF); (tt) capsaicin cream; (uu) Tachykinin NK1 and NK3 receptor antagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; and (vv) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892.